Many dialkylnitrosamines are powerful carcinogens. They are widely dispersed in the environment and human exposure occurs through foods, cosmetics, pollutants, alcohol and tobacco products, and industrial processes. This laboratory has been engaged in a detailed analysis of the chemistry of the reactive intermediates with a view to a quantitative understanding of the lifetimes of these intermediates, the mechanisms of their reactions and how lifetimes and mechanisms are affected by structure. It has recently been demonstrated that there are remarkable effects of structure on the reactivity of alpha-hydroxydialkylnitrosamines. A wide-ranging investigation of the effects of structure on reactivity and mechanism is underway and to be continued in the proposed period of support. N-nitrosiminium ions have been proposed as intermediates in the decay of alpha-substituted dialkylnitrosamines. Surprisingly, it has only recently been discovered that N-nitrosiminium ions are ambident electrophiles with nucleophiles reacting at both the iminium ion carbon and the nitroso nitrogen. Elaboration of this chemistry with N and S nucleophiles to determine the generality of this reaction and its dependence on iminium ion structure is a focus of the present proposal. The question of how diazonium ion and nucleophile structure affects alkylating site specificity is central to understanding the molecular basis of nitrosamine carcinogenicity. Our studies and data in the literature have led to the construction of a model for thinking about what controls site selectivity of alkylation as a function of diazonium ion/carbocation structure. This model suggests the studies within that present direct tests of the model and investigations to characterize factors controlling site selectivity. Independent of the survival of the model, the results will generate a rational quantitative framework for addressing site selectivity in the reactions with nucleophilic atoms of nucleosides, and DNA.